1. Field of the Invention
This invention relates to a novel pharmaceutical preparation for oral administration containing cyclosporin(s), a process for producing said pharmaceutical preparation and the use thereof for oral administration.
2. Description of the Prior Art
Cyclosporins are cyclic oligopeptides of lower fungi which have been discovered by scientists at Sandoz AG, Basel. Especially cyclosporin A and cyclosporin G, respectively, have been used as immunosuppressive agents, especially in graft transplants. Also preferred is the cyclosporin derivative "SDZ IMM 125", a hydroxyethyl derivative of D-serine-8-cyclosporin. The use in the case of other diseases, e.g. diabetes and psoriasis as well as numerous autoimmune disorders (e.g. rheumatoid arthritis, endogenous uveitis etc.) has also been described.
Cyclosporin A is obtained as a white amorphous powder from fungi by column chromatography over silica gel, it crystallizes from acetone in the form of white needles having a melting point of from 148 to 151.degree. C. In addition to cyclosporin A, numerous other cyclosporins are known, ranging from cyclosporin A to cyclosporin Z (cf. Rompp's Chemie Lexikon, 9 th edition, pages 841-843). Semisynthetic derivatives of the cyclosporin are known as well and may be employed according to the present invention. Said derivatives are substances being chemically very similar to each other, and consisting of cyclic polypeptides of 11 amino acids, which are partly methylated. Cyclosporins are soluble in alcohol, ether, acetone, chlorinated hydrocarbons and natural oils (triglycerides of fatty acids).
Cyclosporin A is commercially available for oral application in the form of capsules as well as a solution for oral administration. In both presentation forms, the cyclosporin is dissolved in a mixture of ethanol with a vegetable oil (Pharmacopoeia Martindale, 29th edition, U.S. Pharm. XXII, 619, as well as the technical information Sandimmun.RTM. of Sandoz Company).
In addition to ethanol and vegetable oil (preferably corn oil) further adjuvants are used for the dissolution of cyclosporin A and to maintain it in dissolved form, e.g. poly(oxyethylene)-6-glycerol-tri(oleate, linoleate). The use of said adjuvants reveals the great problems involved in the oral administration of cyclosporin in a form which ensures at least partial resorption thereof.
The poly(oxyethylene)-6-glycerol-tri-oleates or linoleates used to achieve an improved solubility of the cyclosporins may have undesirable effects, they affect the resorption not only of the cyclosporins, but also of other substances, such as fats, paraffins, vitamins etc. Furthermore, the quantities employed of said adjuvants should not exceed 25 mg per kg body weight. Moreover, these substances may induce undesirable allergic reactions, which may be as intense as shock conditions. The major problem of the application forms of cyclosporin(s) described above for oral administration is that cyclosporin is resorbed poorly and that also this resorption varies widely. Resorption is incomplete and varies highly from patient to patient, even on a daily basis in the same patient. In general, resorption varies between 20 and 50% of the administered dose of cyclosporin(s). However, a uniform and homogenous resorption is extremely desirable. Moreover, it would be practical to have cyclosporin preparations which ensure a better overall resorption, i.e. an increased bioavailability.
Therefore, administration forms have been developed, in which cyclosporin was dissolved in a mixture, containing monoglycerides, diglycerides, triglycerides of fatty acids, alcohol, propylene glycol and macrogol glycerol hydroxystearate. This enables a better and more uniform resorption, but there are patients who show a hypersensitivity against the synthetic adjuvants propylene glycol and macrogol glycerol hydroxystearate.
Therefore, emulsions containing cyclosporin for oral administration have been developed which contain only natural adjuvants, i.e. in addition to water, natural fats, lecithins and alkaline salts of free fatty acids (German disclosure P4338086.7).
Said emulsions ensure an improved and a more uniform resorption of cyclosporin(s), and contain only pharmaceutical adjuvants of natural materials, such as natural fats, lecithins and alkaline salts of edible fatty acids. However, said emulsions suffer from the disadvantage that they essentially can only be administered in the form of a drinking solution. Its administration in capsules, in particular soft gelatin capsules, is not possible or only with significant effort, since the oil in water emulsion may attack the capsule shell.